Allograft rejection constitutes the major impediment to the success of renal transplantation. Chronic rejection is currently the most prevalent cause of renal transplant failure. Clinically, chronic rejection presents by chronic transplant dysfunction, characterized by a slow loss of function, often in combination with proteinuria and hypertension. Chronic rejection develops in grafts that undergo intermittent or persistent damage from cellular and humoral responses resulting from indirect recognition of alloantigens. The most effective option to prevent renal failure from chronic rejection is to avoid graft injury from both immune and nonimmune mechanism together with nonnephrotoxic maintenance immunosuppression. Currently available diagnostic methods, including clinical presentation and biochemical organ function parameters, often fail to detect rejection until late stages of progression.